Tumorsuppressor

The capacity of the immune system to distinguish foreign from self-antigen, and to subsequently eliminate the threat of disease without injuring the host is crucial for survival. It also serves to defend against tumor formation and progression via a process termed cancer immunosurveillance. Innate and adaptive immune cell types and effector molecules collectively function as extrinsic tumorsuppressor mechanisms. However, tumors may escape immunesurveillance through a variety of mechanisms that create a local microenvironment that is unfavorable for effective tumor immunity...

Clear cell renal cell carcinomas are characterized by 3p loss, and by inactivation of Von Hippel Lindau (VHL), a tumorsuppressor gene located at 3p25. Recently, SETD2, located at 3p21, was identified as a new candidate ccRCC tumor-suppressor gene. The combined mutational frequency in ccRCC tumors of VHL and SETD2 suggests that there are still undiscovered tumor-suppressor genes on 3p. We screened all genes on 3p for mutations in 10 primary ccRCC tumors using exome-sequencing. We identified inactivating mutations in VHL, PBRM1, and BAP1...

PI3K/Akt/mTOR and p53 signaling pathways are frequently deregulated in tumors. The anticancer drug RAD001 (everolimus) is a known mTOR-inhibitor, but mTOR-inhibition leads to phosphorylation of Akt inducing resistance against RAD001 treatment. There is growing evidence that conflicting signals transduced by the oncogene Akt and the tumorsuppressor p53 are integrated via negative feedback between the two pathways. We previously showed that the anti-malarial Chloroquine, a 4-alkylamino substituted quinoline, is a p53 activator and reduced the incidence of breast tumors in animal models...

BACKGROUND AND PURPOSE: Maspin (mammary serine protease inhibitor) is a member of the serpin superfamily of protease inhibitors and is known to have tumorsuppressor function in breast and prostate cancers, acting at the level of tumor invasion and metastasis. However, there have been no published data regarding the role of Maspin in squamous cell carcinoma (SCC) and transitional cell carcinoma (TCC) of urinary bladder. PATIENTS AND METHODS: We have evaluated the immunohistochemical expression of Maspin and p53 in a series of 134 bladder cancer patients (56 SCC and 78 TCC) and the interrelationship between clinicopathological features and Maspin and p53 expression...

The human breast and ovarian cancer susceptibility gene BRCA1 is a tumorsuppressor gene which is mutated and lost in hereditary breast and ovarian cancer, and has both alleles mutated in approximately 10-15% of cases of sporadic ovarian cancer. Studies of chromosome loss in ovarian cancer show that at least one allele of the BRCA1 gene is lost or mutated in up to 70% of sporadic ovarian cancers. Although no sporadic breast cancers contain BRCA1 mutations, our published study shows that expression of the mRNA is decreased suggesting that the BRCA1 gene is altered quantitatively in sporadic cancer and qualitatively in hereditary cancer...

Allelic loss of human chromosome sequences contributes to tumorigenesis through the inactivation of putative tumor-suppressor genes. The Knudson hypothesis proposes that deletion or mutation must affect both alleles of the gene in order to disable tumor suppression (1). As might be expected, the effect of "two hits" on tumor-suppressor gene integrity-e.g., deletion of one allele and mutation of the remaining allele-would disable the gene from encoding gene product. The von Hippel-Lindau (VHL) gene is an example of a tumorsuppressor gene that fulfills the Knudson hypothesis-e...

In a mouse melanoma metastasis model it has been recently shown that ADAM15 overexpression in melanoma cells significantly reduced the number of metastatic nodules on the lung. Unfortunately, the expression of ADAM15 in human melanoma tissue has not been determined so far. In our study, we characterized the expression of ADAM15 in tissue micro-arrays of patients with primary melanoma with melanoma metastasis. ADAM15 was expressed in melanocytes and endothelial cells of benign nevi and melanoma tissue. Importantly, ADAM15 was significantly downregulated in melanoma metastasis compared to primary melanoma...

UNLABELLED: Changes of the DNA methylation pattern are proven to be an important process during tumorigenesis. This event can occur in several manners in the tumor microenvironment and there are still not any effective and high-throughput methods for genome-wide analysis of this phenomenon. AIMS: Our aim was to identify colorectal cancer development and progression specific marker genes regulated by DNA methylation using gene expression analysis. In this study we present a gene expression-based method combined with a cell culture model, which can be used for a genome-wide analysis of the methylation events during the colorectal tumorigenesis...

BACKGROUND: Breast metastasis of ovarian cancer is rare. A patient with a breast tumor which turned out to be a metastasis as the first clinical manifestation of a primary ovarian cancer diagnosed 56 months later is described. CASE REPORT: A 72-year-old patient presented with a palpable mass in the right breast. Lumpectomy was performed and primary breast cancer was excluded. Histology confirmed a poorly differentiated adenocarcinoma. However, further examination showed no evidence of extramammary primary malignancy...

Primary liver cancer is the fifth most common cancer worldwide. Hepatocellular carcinoma accounts for 85-90% of primary liver cancers. Distribution of hepatocellular carcinoma shows variations among geographic regions and ethnic groups. Males have higher liver cancer rates than females. Hepatocellular carcinoma occurs within an established background of chronic liver disease and cirrhosis (70-90%). Major causes (80%) of hepatocellular carcinoma are hepatitis B, C virus infection, and aflatoxin exposition. Its development is a multistep process...

Endogenous small RNAs (miRNAs) regulate gene expression by mechanisms conserved across metazoans. While the number of verified human miRNAs is still expanding, only few have been functionally annotated. To perform genetic screens for novel functions of miRNAs, we developed a library of vectors expressing the majority of cloned human miRNAs and created corresponding DNA barcode arrays. In a screen for miRNAs that cooperate with oncogenes in cellular transformation, we identified miR-372 and miR-373, each permitting proliferation and tumorigenesis of primary human cells that harbor both oncogenic RAS and active wild-type p53...

Extensive hypermethylation and consecutive transcriptional silencing of tumorsuppressor genes have been documented in multiple tumor entities including breast cancer. In a microarray based genome-wide methylation analysis of five sporadic breast carcinomas we identified a hypermethylated CpG island within the first intron of the prospero related homeobox gene 1 (PROX1). We, therefore, investigated CpG island methylation of PROX1 in a series of 33 pairs of primary breast cancer and corresponding normal tissue samples by bisulfite sequencing and COBRA analyses...

In search of new targeted therapies for squamous cell carcinoma of the head neck (HNSCC), a better understanding of the carcinogenesis is of outmost importance. Recent studies show that not only genetic but also epigenetic alterations initiate the multistep process of tumordevelopment. Epigenetic changes lead to altered gene expression without alterations of the DNA sequence. The best characterized epigenetic change is the methylation of the promoter region of genes, especially of tumorsuppressor genes. The methylation of the promoter region blocks the promoter and therefore represses transcription...

The capacity of glioma cells to invade normal brain leads to far reaching dissemination of these tumors limiting surgical resection and the prospect of local treatment strategies. The analysis of the dissemination pattern, the molecular substrates and mechanisms involved suggest that glioma invasion most likely represents independent cellular behaviors leading to distinct pattern of spread. The search for common denominators of the invasive phenotype has demonstrated that invasive cells show gene expression profiles indicating elevated expression of motility associated genes and genes involved in resistance to apoptosis whereas proliferation and apoptosis related gene expression is repressed...

To study the relationship between abnormal expression of oncogene protein and HBV replication, we detected the expression of protein products C-erbB-2 P185, ras P21 and tumorsuppressor gene product P53 and HBeAg in the serum of 64 patients with chronic HBV infection by using immunohistochemical technique and ELISA. The results were as follows. The positive detection rates of serum HBeAg in C-erbB-2 P185 and ras P21 oncogenes positive groups were 89.4% and 84.6% respectively, but only 20% and 48% in C-erbB-2 P185 and ras P21 negative groups...

BACKGROUND AND AIMS: Trefoil peptides (TFF1, TFF2 and TFF3) are acute phase proteins up-regulated in response to gastrointestinal mucosal damage. They promote cell migration, protect and heal the mucosa and may function as tumorsuppressors. We assumed them to be regulated by the proinflammatory cytokines interleukin-1beta (IL1beta) and interleukin-6 (IL6), which trigger the transcriptional factors NF-kappaB and C/EBPbeta. METHODS: Following IL1beta and IL6 stimulation, expression of TFF genes was analyzed in gastrointestinal cell lines HT-29 and KATO III by reporter gene assays using TFF promoter constructs and by quantitative real-time PCR...

Different processing of the leaves of the tea plant Camellia sinensis yields green or black tea, the subject of numerous investigations on the preventive effects on chronic degenerative diseases. The tea polyphenols, in particular (-)-epigallocatechin gallate (EGCG) were found to account for most of the protective effects. Since the concentration of EGCG is 5 times higher in green than in black tea, it is assumed that green tea possesses a greater preventive potential. Protection against cancer and cardiovascular diseases are the most important biomedical effects...

To investigate whether the tumor suppressor p53 protein, an indicator of DNA damage and cell stress, accumulates in the course of influenza-virus-induced murine pneumonia at the site of inflammation, female BALB/c mice were infected each with 5 x 10(4) infectious units of influenza virus A, strain Puerto Rico (PR) 8, by instillation into the nose and the pharynx. Two days later the mice became sick. Three and 6 days after infection the lungs of sacrificed infected and uninfected mice were examined. We assessed the presence and localisation of inflammation, the expression of influenza viral and p53 protein, as well as of the WAF1/Cip1/SDI gene product p21...

Normal human somatic cells have a finite life span in vivo as well as in vitro and retire into senescence after a predictable time. Cellular senescence is triggered by the activation of two interdependent mechanisms. One induces irreversible cell cycle exit involving activation of two tumorsuppressor genes, p53 and pRb, and the proper time point is indicated by a critical shortening of chromosomal ends due to the end-replication problem of DNA synthesis. The development of a malignant cancer cell is only possible when both mechanisms are circumvented...

An allelotype covering all autosomes was constructed for the embryonal form of childhood rhabdomyosarcoma (ERMS) in order to identify regions encompassing tumorsuppressor genes (TSG) involved in ERMS. Thusfar most studies were focussed on chromosome 11p15.5, which frequently shows loss of heterozygozity (LOH) in embryonal tumors like RMS and Wilms' tumor (WT). In this study we show that, besides LOH of chromosome 11p15.5 (72%), LOH of chromosome 16q was present in 54% of the tumors analysed. Delineation of these two regions shows that the smallest region of overlap (SRO) for chromosome 11 was between D11S988 and D11S922...